Protein misfolding arises in many neurodegenerative diseases. The mechanisms by which protein misfolding causes cell death and disease are poorly understood. The broad, long-term research objectives are: 1) to decipher the cellular, molecular, and genetic mechanisms that cause neurodegeneration, and 2) to develop new therapies to prevent and treat neurodegenerative diseases through correction of cellular protein misfolding in people. The Unfolded Protein Response (UPR) is a conserved intracellular signal transduction mechanism essential for cellular protein homeostasis. The UPR activates transcriptional programs that induce chaperones, protein folding enzymes, and protein degradation pathways (proteasome and autophagy). The UPR also regulates the speed of translation to match the amount of newly synthesized polypeptides to cellular protein folding capacity. If protein misfolding persists, the UPR triggers apoptosis. The UPR may be a potential pathomechanism underlying diseases arising from protein misfolding. PERK encodes a serine/threonine kinase that regulates the UPR. In people, GWAS identified PERK as a genetic risk factor for the tauopathy neurodegenerative disease, Progressive Supranuclear Palsy (PSP). This research investigates how PERK causes PSP in these Specific Aims. Aim 1 will investigate PERK's role in mediating neurodegeneration caused by environmental chemical toxins that increase risk of tauopathy. PERK activity will be assessed in human stem cell-derived neurons treated with PSP-linked agents. Small molecule proteostasis agents will be tested for their efficacy in rescuing neuronal damage linked to environment agents. Aim 2 will analyze the enzymatic properties of PERK heterodimers compared to homodimers. Isogenic stem cell-derived neurons will be employed. In parallel, recombinant PERK heterodimers will be generated and characterized using small molecule heterodimerizering compounds. Aim 3 will investigate the molecular and biochemical basis for selective tau neuropathology in the brain. Postmortem human brain tissues from vulnerable and resistant brain regions will be compared for UPR activity. Genotyped brain cases will be examined to see how risk PERK allele expression affects tau neuropathology. PERK is an essential regulator of protein quality in cells, and human PERK alleles are genetic risk factors for tauopathy neurodegeneration. These studies will have a positive impact by elucidating fundamental molecular pathomechanisms of PERK signaling in PSP. These studies may also reduce the clinical burden of PSP and related tauopathy neurodegenerative diseases by development of novel therapeutic strategies based on pharmacologic regulation of cellular protein quality homeostasis.